title: IL-23R is Epigenetically Regulated and Modulated by Chemotherapy in Non-Small Cell Lung Cancer.
abstract: The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn's disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease.
authors.affiliation: Department of Clinical Medicine, Trinity College Dublin , Dublin , Ireland ; Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital , Dublin , Ireland.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Baird
authors.forename: Eilis
authors.initials: E
authors.lastname: Dockry
authors.forename: Anne
authors.initials: A
authors.lastname: Daly
authors.forename: Emma
authors.initials: E
authors.lastname: Stack
authors.forename: Derek G
authors.initials: DG
authors.lastname: Doherty
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: O'Byrne
authors.forename: Steven G
authors.initials: SG
authors.lastname: Gray
keywords: IL-23R; acetylation; apilimod; epigenetics; methylation; non-small cell lung cancer